Ethanol produces a well recognized spectrum of neurologic sequelae following acute and chronic exposure. The development of tolerance/dependence to this drug, together with the consequent neurodegenerative effects of chronic ethanol abuse pose a major public health concern. Recent studies have documented that ethanol can modulate the expression of specific gene products. This might be the ultimate mechanism in cellular adaptation to chronic ethanol exposure. This proposal describes a comprehensive biochemical/molecular genetic approach to the study of ethanol effects on gene expression in the NG108-15 glioma x neuroblastoma cell line. This system has been well characterized as a model system for studying the biochemistry of ethanol effects on neurons. The goal of this study is the identification and isolation of ethanol responsive genes (ERGs). Initial experiments will extend current studies with Northern blot analysis of specific marker genes that have been shown to respond (induction and inhibition) to chronic ethanol. The effects of ethanol on NG108-15 cell mRNA will also be studied by 2-dimensional gel analysis of ## vitro translation products. These studies will then be extended to include a detailed analysis of protein synthesis in cells exposed to acute or chronic ethanol. Finally, molecular cloning will be used to isolate ERGs. Differential and/or subtractive hybridization screening will be used to select genes that are preferentially modulated by ethanol. The identification and isolation of ERGs may provide powerful molecular probes for the study of ethanol tolerance/dependency both experimental models and in humans. Finally, the cloning of specific ERGs may enable a molecular study of the genetics of alcoholism.